Allergic reactions to hymenoptera stings (bees, bumble bees, yellow jackets, wasps, hornets and the like) are often serious and can be life threatening. It is estimated that 40-50 persons die each year in the United States from insect sting allergy. In a survey of a large adult population in the Baltimore, Md., area, 4% of the population reported a history of systemic sting reactions, while 20% of family members of bee keepers were reported to have systemic reactions. Estimates of hymenoptera sting sensitivity in a general population by history alone ranged between 0.4 and 0.8% of the population. In another study of fatalities due to insect stings, only two of nine fatalities had a positive history of generalized reaction to insect stings. This not only demonstrates the high incidence of sting sensitivity especially in high risk groups and the potential fatalities of such stings but also indicates the importance of predicting serious reactions in high risk individuals. Protection may be natural or induced as a result of immunotherapy or multiple stings over a long period of time such as observed in beekeepers.
Immunotherapy (IT) has been shown to be beneficial for a variety of allergens, particularly for insect sting sensitivity.
Immunotherapy for bee sting sensitivity involves injection of gradually increasing amounts of bee venom (BV) at regular intervals, starting with a minute amount. The regime is empiric but usually when the individual is able to tolerate 50 .mu.g of venom (average amount of venom in a single bee sting) with no systemic reaction, the dose may be increased up to a total dose of 100 .mu.g venom per month and IT maintained at this dose, until a sting without a reaction occurs. Discontinuation of ITA after 5 years if no reaction occurs during this time has been suggested to provide protection for at least two years after cessation of IT. Protection, however, is a complex and dynamic process and may decline upon cessation of immunotherapy. The mechanism(s) by which immunotherapy protects is not completely understood. It has been shown that immunotherapy results in reduction of venom specific IgE and the production of venom specific `blocking` IgG antibodies. These antibodies are closely associated with protection presumably by competing for venom antigens with mast cell bound IgE antibodies and thus preventing histamine release.
Cellular events leading to the increased synthesis and suppression of IgE antibodies have also been described. T cells can release lymphokines which can influence B cells and macrophages in many different ways. T helper and suppressor cells can have profound influence on the production and suppression of IgE synthesis. The influence of IT on the regulatory role of these cells on IgE synthesis is currently under investigation in a number of laboratories. Various IgE specific suppressive and enhancing factors have recently been described. These factors have molecular weights which range from 10,000 to 150,000. In addition to IgE antibodies which are known as the major class of antibodies responsible for the release of histamine and other mediators from sensitized mast cells and basophils, IgG4 antibodies have also been shown to sensitize effector cells in animals and cause mediator release. These antibodies have been found with increased frequency to food antigens in asthmatic patients compared to healthy controls. IgG4 antibody response in bee venom sensitive individuals has been studied and it has been suggested that IgG4 may act as blocking antibody. However in studies of BV sensitive individuals by applicants a clear cut correlation between bee venom specific IgG4 and sensitivity or protection could not be found. Among bee sting sensitive patients, severe or mild systemic reactions occurred in a small percentage of individuals who had low or moderate amounts of IgG4 antibodies to BV, while only one out of 14 individuals who had high levels of IgG4 had a mild systemic reaction to BV and the remainder showed only local reactivity. This may be the case because cells producing IgG4 are mainly found in the mucosal associated lymphoid tissue. Venom specific IgE antibody levels may initially rise but usually fall with IT. Venom specific IgG antibody levels may initially increase but as immunotherapy proceeds IgG levels plateau or even drop in the face of continued protection. Failure of protection even in the presence of adequate levels of specific IgG antibodies as well as protection in the absence of elevation in specific IgG antibodies have been observed. It has been shown that in some cases non-IgE antibodies to allergen(s) may not inhibit the binding of IgE to the allergen(s). Therefore, there may be a discrepancy in the notion that venom specific `blocking` IgG antibody competition for the venom antigen with IgE antibodies is a sole factor in affording protection with bee venom immunotherapy. Taken together these findings point to other factor(s) which may be involved in the modulation of the immune response. Anti-idiotypic antibodies can modulate immune responses and may well be a major influence in protection afforded by IT.
Classically the individual antigenic specificities of antibodies or antigen specific cell receptors are referred to as idiotypes. The individual immunogenic structures in the variable region of homogeneous antibodies or antigen-specific cell receptors are called idiotypes. Antibodies to idiotypes are referred to as anti-idiotypes. The existence of idiotypes and anti-idiotypes, both as soluble immunoglobulins in the serum and as lymphocyte receptors involved in a complex network of interactions that regulate immune response has been demonstrated by many observations. In the strictest sense, every idiotype within the repertoire of possible idiotypes is in turn a self-antigen for complementary anti-idiotype. Hence the mechanisms regulating autologous idiotype should be applicable to any anti-idiotype.
Intentionally induced idiotype suppression by parenteral administration of anti-idiotypic antibodies and the natural occurrence of anti-idiotypic antibodies following immunization with conventional antigens represent clear examples of the potential inhibitory influence of anti-idiotypic antibodies on the immune response. In other instances, it can be shown that anti-idiotypic antibodies enhance the immune response. It seems that the effects produced depend on the idiotypic specificities expressed by the receptors of B cells and by both helper and suppressor T cells involved in the immune response triggered by a particular antigen.
Extensive studies of the antibody response to Benzylpenicilloyl (BPO) and Phosphorylcholine (PC) have been carried out and it has been concluded that idiotypes present on IgE, IgG, IgA and IgM antibodies to these antigens are identical or very similar. Using mouse models for the production of IgE antibodies, it has been shown that anti-BPO antibodies of IgE class could be actively suppressed in mice producing anti-idiotypic antibodies to anti-BPO which could also suppress anti-BPO IgE antibodies by passive transfer of anti-BPO anti-idiotypic antibodies. Moreover, anti-idiotypic antibody production has been shown in the course of a normal immune response. IgG auto-anti-idiotypic antibodies to anti-Rye 1 have been isolated from a single Rye-sensitive patient. These anti-idiotypic antibodies blocked the reaction of IgE and IgG anti-Rye 1 to Rye antigen. The relationship of these antibodies to immunotherapy could not be established because the patient from whom the serum was obtained was on immunotherapy for several years before the serum specimen could be collected. In addition, the role of anti-idiotypic antibodies in the modulation of immune response in this instance could not be established because longitudinal studies were not carried out. Auto-anti-idiotypic antibodies have been detected in normal individuals after booster immunization with tetanus toxoid. These antibodies have been shown to inhibit the synthesis of anti-tetanus toxoid antibodies by peripheral blood lymphocytes of the individuals in vitro. Rabbit anti-idiotypic antibodies against human anti-tetanus toxoid were shown to inhibit in vitro IgE anti-tetanus toxoid synthesis by lymphocytes from individuals producing anti-tetanus toxoid antibodies. The possibility that idiotypic anti-idiotypic interactions play a role in humam T cell response to antigen was also studied in this system. The study showed that rabbit anti-idiotypic antibodies to anti-tetanus toxoid were capable of generating antigen specific suppressor cells when T cells from sensitized individuals were incubated with anti-idiotypic antibodies.
Little is known about the production of auto-anti-idiotypic antibodies in allergic patients during immunotherapy. We hypothesize that anti-idiotypic antibodies reactive against bee venom specific antibodies are produced in multiple stung beekeepers and during bee venom immunotherapy. These antibodies (a) suppress bee venom specific IgE antibody responses, (b) bind to preformed bee venom specific IgE and effectively compete with available bee venom constituents.